Axially chiral NHC-Pd(II) complexes in the oxidative kinetic resolution of secondary alcohols using molecular oxygen as a terminal oxidant

Article abstract of DOI:10.1021/ol063061w

(Chemical Equation Presented) Axially chiral N-heterocyclic carbene (NHC) Pd(II) complexes were prepared from optically active 1,1′-binaphthalenyl- 2,2′-diamine (BINAM) and H₈-BINAM and applied in the oxidative kinetic resolution of secondary alcohols using molecular oxygen as a terminal oxidant. The corresponding sec-alcohols can be obtained in good yields with moderate to good enantioselectivities.

Full text of DOI:10.1021/ol063061w

ORGANIC
LETTERS
2007
Vol. 9, No. 5
865-868
Axially Chiral NHC−Pd(II) Complexes in
the Oxidative Kinetic Resolution of
Secondary Alcohols Using Molecular
Oxygen as a Terminal Oxidant
Tao Chen,† Jia-Jun Jiang,† Qin Xu,† and Min Shi*,†,‡
School of Chemistry & Molecular Engineering, East China UniVersity of Science and
Technology, 130 Mei Long Road, Shanghai 200237 China, and State Key Laboratory
of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
mshi@mail.sioc.ac.cn
Received December 18, 2006
ABSTRACT
Axially chiral N-heterocyclic carbene (NHC) Pd(II) complexes were prepared from optically active 1,1′-binaphthalenyl-2,2′-diamine (BINAM) and
H8-BINAM and applied in the oxidative kinetic resolution of secondary alcohols using molecular oxygen as a terminal oxidant. The corresponding
sec-alcohols can be obtained in good yields with moderate to good enantioselectivities.
The oxidation of alcohols is one of the most common and
important reactions in organic chemistry and has exceptional
useful applications in organic synthesis.1 During the past
decade, palladium-catalyzed aerobic oxidation of alcohols
has received considerable attention due to the economic and
environmental advantages of molecular oxygen as a terminal
oxidant.2,3 Recently, Sigman4 and Stoltz5 independently
developed a convenient method for the enantioselective
aerobic oxidation of secondary alcohols using a (-)-
sparteine/Pd(II) complex as the catalyst, and this has emerged
as a powerful method for the preparation of enantioenriched
(3) For recent reviews, see: (a) Muzart, J. Tetrahedron 2003, 59, 5789-
5816. (b) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400-3420. (c)
Schultz, M. J.; Sigman, M. S. Tetrahedron 2006, 62, 8227-8241. (d)
Sigman, M. S.; Jensen, D. R. Acc. Chem. Res. 2006, 39, 221-229. (e)
Rogers, M. M.; Stahl, S. S. In N-Heterocyclic Carbenes in Transition Metal
Catalysis; Glorius, F., Ed.; Springer: New York, 2007; Vol. 21, pp 21-
46. For some more selected examples, see: (e) Peterson, K. P.; Larock, R.
C. J. Org. Chem. 1998, 63, 3185-3189. (f) Nishimura, T.; Onoue, T.; Ohe,
K.; Uemura, S. J. Org. Chem. 1999, 64, 6750-6755. (g) Brink, G.-J.;
Arends, I. W. C. E.; Sheldon, R. A. Science 2000, 287, 1636-1639. (h)
Steinhoff, B. A.; Stahl, S. S. Org. Lett. 2002, 4, 4179-4181. (i) Schultz,
M. J.; Park, C. C.; Sigman, M. S. Chem. Commun. 2002, 3034-3035. (j)
Jensen, D. R.; Schultz, M. J.; Mueller, J. A.; Sigman, M. S. Angew. Chem.,
Int. Ed. 2003, 42, 3810-3813. (k) Schultz, M. J.; Hamilton, S. S.; Jensen,
D. R.; Sigman, M. S. J. Org. Chem. 2005, 70, 3343-3352.
† East China University of Science and Technology.
‡ Shanghai Institute of Organic Chemistry.
(1) Hudlicky, M. Oxidations in Organic Chemistry; ACS Monograph
Series; American Chemical Society: Washington, DC, 1990.
(2) Lloyd and Schwartz initiated the palladium-catalyzed aerobic oxida-
tion of alcohols; see: (a) Lloyd, W. G. J. Org. Chem. 1967, 32, 2816-
2819. (b) Blackburn, T. F.; Schwartz, J. J. Chem. Soc., Chem. Commun.
1977, 157-158.
10.1021/ol063061w CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/30/2007

alcohols. However, a significant limitation of this system is
the requirement of (-)-sparteine, a chiral tertiary diamine,
which is only readily available as a single antipode and is a
difficult template to optimize through systematic structural
variations.4i On the other hand, the use of N-heterocyclic
carbene (NHC) ligands has developed rapidly in the latest
decade due to their stability to air and moisture and their
strong σ-donor but poor π-acceptor abilities.6 Homogeneous
catalytic reactions using NHC-Pd complexes have been
extensively investigated, and some excellent results have
been achieved.7 Application of chiral NHC-Pd(II) com-
plexes in enantioselective kinetic resolution of secondary
alcohols has also been reported.4i Unfortunately, the results
were not so good when inorganic bases other than the chiral
base (-)-sparteine were used. Herein, we present new chiral
NHC-Pd(II) complex systems as effective catalysts in the
oxidative kinetic resolution of racemic secondary alcohols
using molecular oxygen as the terminal oxidant.
We previously reported the preparation of an axially chiral
NHC-Rh complex derived from optically active 1,1-
binaphthalenyl-2,2′-diamine (BINAM) and demonstrated its
high chiral induction abilities in the hydrosilylation of methyl
ketones.8 These results inspired us to synthesize similarly
axial chiral cis-chelated NHC-Pd(II) complexes 1 and 2 and
to apply them in the oxidative kinetic resolution of secondary
alcohols (Figure 1).9 The synthesis of NHC-Pd(II) com-
Figure 2. ORTEP drawing of chiral NHC-Pd(II) complex 2.
In optimization studies, the oxidation of 1-phenylethanol
to acetophenone using racemic complex 1 was selected as a
model reaction to screen a series of bases and solvents. The
results are summarized in Tables 1 and 2, respectively.12 We
found that (1) organic bases were generally inefficient under
identical conditions (Table 1, entries 10-13), (2) K2CO3,
Cs2CO3, K3PO4‚3H2O, KOtBu were the promising bases
(Table 1, entries 2, 3, 6, and 8), and (3) PhMe and DMF
were the solvents of choice (Table 2, entries 1-7).13
Next, the enantioselective oxidative kinetic resolution of
1-phenylethanol was evaluated using chiral complex 1. The
results are summarized in Table 3.13 It was found that PhMe
was the solvent of choice and Cs2CO3 was the preferred base
for the kinetic resolution, with this combination furnishing
optically active 1-phenylethanol in 62% conversion and 87%
ee (krel ) 8.80) at 80 °C (Table 3, entry 7). To test whether
Figure 1. Axially chiral NHC-Pd(II) complexes.
plexes 1 and 2 was accomplished by use of optically active
BINAM and H8-BINAM as the starting materials in a similar
sequence as in the preparation of the axially chiral NHC-
Rh complex.10 The H8-BINAM was produced by reduction
of BINAM with Pd/C-H2. The structure of 2 was determined
by X-ray diffraction and is shown in Figure 2.11
(7) Selected examples, see: (a) Batey, R. A.; Shen, M.; Lough, A. J.
Org. Lett. 2002, 4, 1411-1414. (b) Navarro, O.; Kaur, H.; Mahjoor, P.;
Nolan, S. P. J. Org. Chem. 2004, 69, 3173-3180. (c) Xu, Q.; Duan, W.
L.; Lei, Z. Y.; Zhu, Z. B.; Shi, M. Tetrahedron 2005, 61, 11225-11229.
(d) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan,
S. P. J. Am. Chem. Soc. 2006, 128, 4101-4111.
(8) Duan, W. L.; Shi, M.; Rong, G. B. Chem. Commun. 2003, 2916-
2917.
(4) (a) Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc.
2001, 123, 7475-7476. (b) Mueller, J. A.; Jensen, D. R.; Sigman, M. S. J.
Am. Chem. Soc. 2002, 124, 8202-8203. (c) Mandal, S. K.; Jensen, D. R.;
Pugsley, J. S.; Sigman, M. S. J. Org. Chem. 2003, 68, 4600-4603. (d)
Mueller, J. A.; Sigman, M. S. J. Am. Chem. Soc. 2003, 125, 7005-7013.
(e) Mandal, S. K.; Sigman, M. S. J. Org. Chem. 2003, 68, 7535-7537. (f)
Mueller, J. A.; Goller, C. P.; Sigman, M. S. J. Am. Chem. Soc. 2004, 126,
9724-9734. (g) Schultz, M. J.; Hamilton, S. S.; Jensen, D. R.; Sigman, M.
S. J. Org. Chem. 2005, 70, 3343-3352. (h) Mueller, J. A.; Cowell, A.;
Chandler, B. D.; Sigman, M. S. J. Am. Chem. Soc. 2005, 127, 14817-
14824. (i) Jensen, D. R.; Sigman, M. S. Org. Lett. 2003, 5, 63-65.
(5) (a) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725-
7726. (b) Bagdanoff, J. T.; Ferreira, E. M.; Stoltz, B. M. Org. Lett. 2003,
5, 835-837. (c) Bagdanoff, J. T.; Stoltz, B. M. Angew. Chem., Int. Ed.
2004, 43, 353-357. (d) Trend, R. M.; Stoltz, B. M. J. Am. Chem. Soc.
2004, 126, 4482-4483.
(9) The X-ray crystal data of racemic NHC-Pd(II) complex 1 has been
deposited in CCDC with number 209242. For the details, see ref 7c. For a
review of practical issues in kinetic resolutions, see: Keith, J. M.; Larrow,
J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001, 343, 5-26.
(10) See the Supporting Information for details.
(11) The crystal data of chiral NHC-Pd(II) complex 2 has been deposited
in CCDC with number 603240: empirical formula, C37H36Cl2N4I2Pd;
formula weight, 967.80; crystal color, habit, colorless, prismatic; crystal
system, orthorhombic; lattice type, primitive; lattice parameters, a )
12.8832(8) Å, b ) 14.0578(9) Å, c ) 209.2839(13) Å, R ) 90°, â ) 90°,
γ ) 90°, V ) 3673.6(4) Å3; space group, P2(1)2(1)2(1); Z ) 4; Dcalc
)
1.750 g/cm3; F000 ) 1888; diffractometer, Rigaku AFC7R; residuals, R,
Rw, 0.543, 0.1246.
(12) Based on the structural similarity of NHC-Pd(II) complexes 1 and
2 with PdCl2/(-)-sparteine (ref 5a), we initiated our investigation with the
same model reaction and similar reaction conditions.
(13) For detailed procedures of base and solvent screening trials, and
the general procedure for the oxidative kinetic resolution of secondary
alcohols, see the Supporting Information.
(6) For reviews, see: (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2002,
41, 1209-1309. (b) Ce´sar, V.; Bellemin-Laponnaz, S.; Gade, L. H. Chem.
Soc. ReV. 2004, 33, 619-636.
866
Org. Lett., Vol. 9, No. 5, 2007

Table 1. Screening for Bases in the Racemic NHC-Pd(II)
Complex 1 Catalyzed Oxidation of 1-Phenylethanol to
Acetophenone
Table 3. Screening for the Best Conditions in the Axially
Chiral NHC-Pd(II) Complex Catalyzed Oxidative Kinetic
Resolution of 1-Phenylethanol
entry
base
conversiona (%)
com-
plex
convb eec (%)
entrya (mol %) MS
base
solvent (%) (config)d krel
e
1
2
3
4
5
6
7
8
9b
10
11
12
13
Na2CO3
K2CO3
Cs2CO3
KF
NaOAc
K3PO4‚3H2O
NaHCO3
KOtBu
13
44
58
5
N.R.
53
12
52
N.R.
6
1
2
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
3A Cs2CO3
3A K2CO3
PhMe
PhMe
37
20
34
25
50
60
62
10
36
61
20
43
36
27
61
67
63
65
N.D.f
N.D.
3
3A K3PO4‚3H2O PhMe
N.D.
4
3A KOtBu
3A Cs2CO3
PhMe
DMF
N.D.
8 (S)
5
1.26
8.97
8.80
6
1 (10) 3A Cs2CO3
1 (10) 4A Cs2CO3
1 (10) 4A Cs2CO3
1 (10) 4A Cs2CO3
1 (10) 5A Cs2CO3
1 (10) 4A K2CO3
PhMe
PhMe
hexane
xylene
PhMe
PhMe
84 (S)
87 (S)
N.D.
40 (S)
86 (S)
22 (S)
36 (S)
34 (S)
7
8
9
8.71
9.06
1.32
3.96
5.61
10
11
12
13
14g
15h
16
17
18
DBU
DMAP
Et3N
N.R.
7
7
1 (10) 4A K3PO4‚3H2O PhMe
1 (10) 4A KOtBu
1 (10) 4A Cs2CO3
1 (10) 4A Cs2CO3
2 (10) 3A Cs2CO3
2 (10) 4A Cs2CO3
2 (10) 5A Cs2CO3
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
30 (S) 12.81
pyridine
83 (S)
93 (S)
88 (S)
87 (S)
8.03
8.35
8.58
7.29
a Conversions were analyzed by GC. b No base was added.
a 1.0 atm of O2, 0.1 M substrate concentration in PhMe. b Measured by
GC. c Measured by chiral HPLC. Some of ee could not be analyzed due to
that the conversions are too low. d Determined by comparison of the sign
the resolution can be done at lower temperature, we
conducted the reaction at 60 °C (Table 3, entry 14).
Disappointingly, the conversion was rather low. Upon
e
of optical rotation to literature values. krel ) ln[(1 - C)(1 - ee)]/ln[(1 -
C)(1 + ee)]. f Not determined. g The reaction was conducted at 60 °C. h The
reaction was conducted at 100 °C.
Table 2. Screening for Solvents in the Racemic NHC-Pd(II)
Complex 1 Catalyzed Oxidation of 1-Phenylethanol to
Acetophenone
entries 6, 7, 10, 16-18).14 As a consequence, the reason for
this combination of 1 with 4 Å and 2 with 3 Å MS gave
better results, although the reason for this remains obscure.
With the optimized conditions in hand, we next investi-
gated the substrate scope of this process. The results are
summarized in Table 4. It can be seen from Table 4 that a
broad range of substrates can be used in this oxidative kinetic
resolution, with 60-82% conversion and 63-99.7% ee
(>99% ee) (krel ) 3.83-19.80) being observed. In addition,
substrates with an electron-withdrawing substituent on the
aromatic ring provided better results on ee than 1-p-
tolylethanol and 1-p-methoxyphenylethanol, with 60-75%
conversion and 77-93% ee being observed (Table 4, entries
1-5, 7-10). Under identical conditions, complex 2 gave the
better results on ee in the presence of molecular sieves 3 Å
to produce the corresponding optically active secondary
alcohols in 77-99.7% ee (>99% ee) with 61-82% conver-
sion along with krel ) 5.52-19.80, presumably due to its
steric bulkiness and the flexibility of backbone skeleton.
Moreover, it is noteworthy that, compared to NHC complex
1, complex 2 generally gave faster resolution rates for the
substrates with an electron-withdrawing substituent on the
aromatic ring, and thus higher ees and higher conversions
can be achieved within shorter reaction times (Table 4, entries
1-4, 12, 13). When the reaction time was prolonged to 24
entry
solvent
conversiona (%)
1
2
3
4
5
6
7
PhMe
MeCN
benzene
DMF
DCE (ClCH2CH2Cl)
DMSO
58
21
11
76
11
18
5
t-BuOH
a Conversions were analyzed by GC.
elevating the temperature to 100 °C, the conversion remained
constant, but the ee showed a slight decrease (83% ee) (Table
3, entry 15). For complex 2, 93% ee and 67% conversion
(krel ) 8.35) could be realized at 80 °C in the presence of 3
Å MS (Table 3, entry 16). Therefore, these best reaction
conditions for the oxidative kinetic resolution of secondary
alcohols were to carry out the reaction in PhMe at 80 °C
using the chiral NHC-Pd(II) complex (10 mol %) as a
catalyst in the presence of molecular sieves 3 Å, 4 Å, or 5
Å. Different molecular sieves were found to have varied
influence on the results under identical conditions (Table 3,
(14) For the role of molecular sieves in Pd-catalyzed aerobic alcohol
oxidation, see: Steinhoff, B. A.; King, A. E.; Stahl, S. S. J. Org. Chem.
2006, 71, 1861-1868.
Org. Lett., Vol. 9, No. 5, 2007
867

of complex 2 (Table 2, entry 6). Upon increasing the size of
the R2 group, a decrease in the krel was observed (Table 4,
entries 8, 11, 13-15). As for naphthyl, heteroaromatic, and
alkenyl substrates, moderate to good enantioselectivities were
also realized under the standard conditions (Table 4, entries
17-21). In general, moderate krel values from 3.83 to 9.45
were obtained with these chiral NHC-Pd(II) complexes 1
and 2. To our delight, 1,2,3,4-tetrahydronaphthalen-1-ol gave
promising resolution results, with selectivity factors of 15.52
and 19.80 in the presence of complexes 1 and 2, respectively
(Table 4, entries 22 and 23).
Table 4. Axially Chiral NHC-Pd(II) Complexes Catalyzed
Oxidative Kinetic Resolution of Secondary Alcohols
On a preparative scale of 1-phenylethanol (1.0 g) with
complex 2 as a catalyst, the alcohol was isolated in 30%
yield with 91% ee along with acetophenone in 60% yield in
the presence of molecular sieves 3 Å within 48 h.
In conclusion, we have developed effective chiral NHC-
Pd(II) complex systems for the oxidative kinetic resolution
of secondary alcohols using molecular oxygen as a terminal
oxidant. The resolution employs a chiral NHC-Pd(II)
complex as catalyst in conjunction with an inorganic base.
Compared to (-)-sparteine/Pd(II) system, the catalyst system
enables us to get sec-alcohols of different configuration
readily through modulating the configuration of NHC-Pd-
(II) complex. Efforts to elucidate the mechanistic details of
this catalytic system and to further optimize the structure of
catalyst are currently in progress.
Acknowledgment. We thank the Shanghai Municipal
Committee of Science and Technology (04JC14083,
06XD14005), Chinese Academy of Sciences (KGCX2-210-
01), and the National Natural Science Foundation of China
for financial support (20472096, 203900502, and 20672127)
and the Cheung Kong Scholar program.
a 1.0 atm of O2, 0.1 M substrate concentration in PhMe. b Measured by
GC. c Measured by chiral HPLC. d Determined by comparison of the sign
of optical rotation to literature values. krel ) ln[(1 - C)(1 - ee)]/ln[(1 -
C)(1 + ee)].
Supporting Information Available: Experimental details
and characterization data, chiral HPLC, and X-ray crystal-
lographic files (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
e
h, up to 98% ee could be obtained, with 82% conversion
(krel ) 5.96) of 1-(4-chlorophenyl)ethanol in the presence
OL063061W
868
Org. Lett., Vol. 9, No. 5, 2007